The present invention relates to an improved method of preparing a series of novel indazole analogs that are selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF.
Since the recognition that cyclic adenosine phosphate (AMP) is an intracellular second messenger, E. W. Sutherland, and T. W. Rall, Pharmacol. Rev., 12, 265, (1960), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized, J. A. Beavo et al., TiPS, 11, 150, (1990), and their selective inhibition has led to improved drug therapy, C. D. Nicholson, M. S. Hahid, TiPS, 12, 19, (1991). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release, M. W. Verghese et al., J. Mol. Cell Cardiol., 12 (Suppl. II), S 61, (1989) and airway smooth muscle relaxation (T. J. Torphy in "Directions for New Anti-Asthma Drugs," eds. S. R. O'Donnell and C. G. A. Persson, 1988, 37 Birkhauser-Verlag). Thus, compounds that selectively inhibit PDE type IV by exhibiting low levels of activity against other PDE receptor types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
An especially useful class of selective PDE4 inhibitors is that disclosed in U.S. application Ser. No. 08/963904, filed Apr. 1, 1997 (Attorney Docket No. PC9281B), which is a continuation-in-part of U.S. provisional application Ser. No. 60/016861, filed May 3, 1996 (Attorney Docket No. 9281), now abandoned; and in international application Ser. No. PCT/IB97/00323 based on said provisional application, filed Apr. 1, 1997 (Attorney Docket No. PC9281A), designating the United Sates, and published as WO 97/42174 on Nov. 13, 1997. Both of said applications are incorporated herein by reference in their entireties.
The class of selective PDE4 inhibitors disclosed in the above-mentioned applications may be prepared in accordance with the synthesis procedures described in U.S. provisional application Ser. No. 60/046858, filed May 8, 1997 (Attorney Docket No. 9798), now abandoned; and in international application Ser. No. PCT/IB98/00647 based on said provisional application, filed Apr. 28, 1998 (Attorney Docket No. PC9798A), designating the United Sates, and published as WO 98/***** on November **, 1998. Both of said applications are incorporated herein by reference in their entireties for their disclosure of the state of the art with respect to preparation of indazole carboxylic acid PDE4 inhibitors. However, there is no suggestion therein of the preparation process of the present invention.
The above-mentioned class of indazole carboxylic acid selective PDE4 inhibitors comprises compounds of Formula (II): ##STR5## and pharmaceutically acceptable salts thereof, wherein R is hydrogen, (C.sub.1 -C.sub.6) alkyl, (--CH.sub.2).sub.n (C.sub.3 -C.sub.7) cycloalkyl wherein n is 0 to 2, or --(Z').sub.b (C.sub.6 -C.sub.10) aryl wherein b is independently 0 or 1, and Z' is (C.sub.1 -C.sub.6) alkylene or (C.sub.2 -C.sub.6)-alkenylene, and wherein said alkyl and aryl moieties of said R groups are optionally substituted by one or more substituents independently selected from halo, hydroxy, (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.5) alkoxy, or trifluoromethyl;
R.sub.1 is hydrogen, (C.sub.1 -C.sub.7) alkyl, phenyl, or (C.sub.3 -C.sub.7) cycloalkyl, wherein said alkyl and phenyl R.sub.1 groups are optionally substituted with up to 3 substituents independently selected from the group consisting of methyl, ethyl, trifluoromethyl, and halo; and PA2 R.sub.2.sup.a and R.sub.2.sup.b are independently selected from the group consisting essentially of hydrogen and recited substituents, provided that one, but not both of R.sub.2.sup.a and R.sub.2.sup.b must be independently selected as hydrogen, wherein said substituents comprise, among others those of Formula (IIa): ##STR6## wherein the dashed lines in formula (Ia) independently and optionally represent a single or double bond, provided that in formula (Ia) both dashed lines cannot both represent double bonds at the same time. PA2 (a) treating a compound of Formula (Ia): ##STR10## wherein R and R.sup.1 are as defined above, with an alcohol comprising a compound of Formula (Ib-A) and an acid comprising a compound of Formula (Ib-B): ##STR11## where R.sub.a is as defined above; and HX is an acid selected from the group consisting essentially of hydrobromic acid; hydrochloric acid; sulfuric acid; sulfonic acid; and aliphatic and aromatic sulfonic acids selected from the group consisting essentially of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, benzylsulfonic acid, p-toluene sulfonic acid, and camphorsulfonic acid, whereby HX provides the acidic conditions which result in formation of a salt of the corresponding imidate of Formula (Ic): ##STR12## and (b) hydrolyzing said compound of Formula (Ic) to provide said compound of Formula (I). PA2 (b) separating and purifying said salt of Formula (Ig.sup.2); followed by: PA2 (c) converting said salt of Formula (Ig.sup.2) back to said free base indazole of Formula (Ig) by treating it with an aqueous base selected from the group consisting essentially of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, preferably sodium hydroxide, to provide said compound of Formula (Ig).
Within the above-described class of PDE4 inhibitors, is a group of especially active compounds in which R.sub.2, which includes and refers to "R.sub.2.sup.a " and "R.sub.2.sup.b ", is a group of formula (Ia) wherein the dashed line attached to the ring carbon atom to which R.sub.3 is attached represents a single bond, m is 0, R.sub.5 is hydrogen and R.sub.4 is --OH, --CH.sub.2 OH, --C(CH.sub.3).sub.2 OH, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 CH.sub.2 CH.sub.3, or --CH.sub.2 C(O)NH.sub.2. Further of particular interest within the above-described group of compounds are those wherein R.sub.3 is cyano, R.sub.4 is --CO.sub.2 H, R is cyclohexyl, cyclopentyl, cyclobutyl, methylenecyclopropyl, isopropyl, phenyl or 4-fluoro-phenyl, and particularly wherein R is cyclohexyl; and R.sub.1 is (C.sub.1 -C.sub.2) alkyl optionally substituted by up to three fluorines, and particularly wherein R.sub.1 is ethyl. It is also important among the above-described group of compounds that R.sub.3 and R.sub.5 are cis as represented in Formula (IIb): ##STR7##
Among the most preferred species of compounds as above-described are the following:
Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid; and PA1 Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester. PA1 R is selected from the group consisting essentially of hydrogen; (C.sub.1 -C.sub.6) alkyl; --(CH.sub.2).sub.n (C.sub.3 -C.sub.7) cycloalkyl wherein n is 0 to 2; and --(Z').sub.b (C.sub.6 -C.sub.10) aryl wherein b is independently 0 or 1, and Z' is (C.sub.1 -C.sub.6) alkylene or (C.sub.2 -C.sub.6) alkenylene; wherein said alkyl and aryl moieties of said R groups are optionally substituted by one or more substituents independently selected from the group consisting essentially of halo, preferably F or Cl; hydroxy; (C.sub.1 -C.sub.5) alkyl; (C.sub.1 -C.sub.5) alkoxy; and trifluoromethyl; and PA1 R.sup.1 is selected from the group consisting essentially of hydrogen; (C.sub.1 -C.sub.6) alkyl; phenyl; and (C.sub.3 -C.sub.7) cycloalkyl; wherein said alkyl and phenyl R.sup.1 groups are optionally substituted with up to 3 substituents independently selected from the group consisting essentially of methyl, ethyl, trifluoromethyl, and halo; PA1 comprising: PA1 R.sup.1.sub.a is selected from the group consisting essentially of (C.sub.1 -C.sub.6) alkyl optionally substituted with up to 3 substituents independently selected from the group consisting essentially of trifluoromethyl, fluoro and chloro. PA1 R is selected from the group consisting essentially of hydrogen; (C.sub.1 -C.sub.6) alkyl; --(CH.sub.2).sub.n (C.sub.3 -C.sub.7) cycloalkyl wherein n is 0 to 2; and --(Z').sub.b (C.sub.6 -C.sub.10) aryl wherein b is independently 0 or 1; and Z' is (C.sub.1 -C.sub.6) alkylene or (C.sub.2 -C.sub.6) alkenylene; wherein said alkyl and aryl moieties optionally substituted by one or more substituents independently selected from the group consisting essentially of halo, preferably F or Cl, hydroxy, (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.5) alkoxy, or trifluoromethyl; PA1 R.sup.1 is selected from the group consisting essentially of hydrogen; (C.sub.1 -C.sub.6) alkyl; phenyl; and (C.sub.3 -C.sub.7) cycloalkyl; wherein said alkyl and phenyl groups are optionally substituted with up to 3 substituents independently selected from the group consisting essentially of methyl, ethyl, trifluoromethyl, and halo; and PA1 [HX] represents an optional salt formed with the basic imino group of the (Ic.sup.2) compound by treatment thereof with an acid selected from the group consisting essentially of hydrochloric acid; hydrobromic acid; sulfuric acid; sulfonic acid, and aliphatic and aromatic sulfonic acids selected from the group consisting essentially of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, benzylsulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; preferably hydrochloric acid,
The above-identified preferred compounds may be represented by Formulas (IIc) and (IId): ##STR8##